The designation ".alpha..sub.1A " is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated ".alpha..sub.1C " cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). However, the designation .alpha..sub.1C is used throughout this application and the supporting tables and figures to refer to the receptor subtype recently renamed ".alpha..sub.1A ". Since in both the old and new nomenclature there has only been one unique receptor subtype which has been designated .alpha..sub.1C (i.e., there is no .alpha..sub.1C under the current nomenclature), ".alpha..sub.1C " is an unambiguous description of this unique receptor subtype.
Incontinence is a condition characterized by the involuntary loss of urine. It can be divided generally into two types, the first involving an unstable bladder as the underlying cause, and the second involving an insufficiency in bladder outlet closing pressure despite the presence of a stable bladder. The condition may arise from a variety of different pathological, anatomical or neurological factors (Lundberg, 1989).
While the prevalence in females is two fold higher, it also affects males (Lundberg, 1989). The greatest incidence is seen in postmenopausal women. It is estimated that at least 10 million Americans suffer from urinary incontinence (Sand et al., 1990). Incontinence can be treated by surgical and nonsurgical methods. Conservative approaches include physiotherapy (Kegel exercises) and functional electrical stimulation which aim to strengthen the peri-urethral musculature (Walters et al., 1992). Periurethral injection of polytetraflurorethylene is a more invasive procedure intended to augment the urethral support (Sand et al, 1990). The most radical treatment for stress incontinence is surgery, involving a variety of techniques which seek to improve the alignment of the bladder, urethra, and surrounding structures.
A variety of pharmaceutical agents have been employed with varying success to treat urinary incontinence. Drugs useful in reducing the contractility of the bladder include anticholinergics, .beta.-blockers, calcium channel blockers, and tricyclic antidepressants. Estrogen has been used with some success in increasing bladder outlet resistance, particularly in postmenopausal women. Its actions have been attributed to a "mucosal seal effect" resulting from urethral mucosal cell proliferation (Wein, 1987), although there is now some suggestion that it may also contribute to a restoration of .alpha.-adrenoceptor expression in the urethra (Wein, 1987).
The most commonly employed agents for increasing bladder outlet resistance are the .alpha.-adrenoceptor agonists. These activate .alpha.-adrenoceptors located on the smooth muscle cells of the proximal urethra and bladder neck (Sourander, 1990; Wein, 1987), resulting in contraction and increased closing pressure. The compounds currently employed for this therapy include the non-selective adrenoceptor agents phenylpropanolamine, ephedrine, and phenylephrine (Wein, 1987; Lundberg, 1989). The actions of these drugs are attributable, in part, to direct activation of adrenoceptors and in part to their ability to displace endogenous norepinephrine from sympathetic neurons following uptake into the nerve terminal, a so-called indirect sympathomimetic action (Andersson and Sjogren, 1982). Their lack of selectivity (see Table 3 hereinafter) among the adrenoceptor subtypes and the indirect action of these compounds results in their activating .alpha..sub.1 -, .alpha..sub.2 -, and .beta.-adrenoceptors in the CNS and in the periphery. As a result, any desired therapeutic effect of these agents may be accompanied by a constellation of undesirable side effects. One major side effect of their use in incontinence is an increase in blood pressure. This effect is dose-dependent and limits the ability to achieve therapeutically effective circulating concentrations of the drug (Andersson and Sjogren, 1982). In addition, these compounds in some patients produce insomnia, anxiety and dizziness as a result of their stimulant actions in the CNS (Andersson and Sjogren, 1982, Wein, 1987).
Another compound which has been evaluated in urinary incontinence is midodrine, a prodrug which is converted in vivo to the active phenylethylamine ST-1059. The clinical efficacy of midodrine has not been demonstrated conclusively (Andersson and Sjogren, 1982). Like the above compounds, its effects may be limited by cross-reactivity with other adrenoceptors (see Table 3) which may limit the maximum achievable dose. A better understanding of the subtypes of .alpha.-adrenoceptors and their involvement in various physiological processes will facilitate the development of more efficacious drugs for the treatment of incontinence. The .alpha.-adrenoceptors are specific neuroreceptor proteins located in the peripheral and central nervous systems and on tissues throughout the body. The receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. Drugs which interact at these receptors comprise two main classes: agonists, which mimic the endogenous ligands (norepinephrine and epinephrine) in their ability to activate the receptor; and antagonists, which serve to block the actions of the endogenous ligands. Many .alpha.-adrenoceptor drugs of both classes have been developed over the past 40 years. Examples in addition to those indicated above, which owe at least part of their action to stimulation of alpha adrenoceptors, include clonidine (agonist; treatment of hypertension), prazosin (antagonist; hypertension), oxymetazoline (agonist, nasal decongestion), and methoxamine (treatment of episodes supraventricular tachycardia). While many of these drugs are effective, they also produce undesirable side effects at therapeutic doses (e.g., clonidine produces dry mouth, sedation and orthostatic hypotension in addition to its antihypertensive effect). During the past 15 years a more precise understanding of .alpha.-adrenoceptors and drugs targeting .alpha.-adrenoceptors has emerged. Prior to 1977, only one .alpha.-adrenoceptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two .alpha.-adrenoceptors, .alpha..sub.1 and .alpha..sub.2, existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six distinct .alpha.-adrenoceptor proteins which are distributed throughout the central and peripheral nervous systems: .alpha..sub.1A, .alpha..sub.1B, .alpha..sub.1C, .alpha..sub.2A, .alpha..sub.2B and .alpha..sub.2C (Bylund, 1992). In addition to the cloned .alpha.-adrenoceptors, several putative .alpha..sub.1 adrenoceptor subtypes have been recently described based upon functional studies in a variety of mammalian tissues. These receptors, which have not been cloned, are described as .alpha..sub.1H, .alpha..sub.1L and .alpha..sub.1N (Murmamatsu, 1995) or "atypical .alpha..sub.1 " (Abel, 1995) adrenoceptors. The precise role of each of the subtypes in various physiological responses is only beginning to be understood, but it is clear that distinct subtypes do mediate distinct physiological responses to agonists and antagonists. For example, it has been shown that norepinephrine-induced contractions of the human prostate are mediated by the .alpha..sub.1C -adrenoceptor (Forray et al., 1994). Many adrenoceptor drugs developed before 1992 are not selective for any particular .alpha.-adrenoceptor subtype. It is increasingly evident that this lack of receptor subtype selectivity is an underlying cause of the untoward side-effects of these drugs.
The role of the sympathetic adrenergic nervous system in the storage function of the bladder is well recognized (Wein, 1987; Latifpour et al, 1990). Likewise, it is understood in the art that the study of adrenoceptor mechanisms in isolated urethra and bladder tissues is applicable to incontinence therapy (Latifpour et al., 1994; Tsujimoto et al., 1986). Various groups have attempted to identify, through binding and functional studies, .alpha..sub.1 receptor subtypes in the urethrae of humans, rabbits, and rats (Yoshida et al., 1991; Testa et al. 1993; Chess-Williams et al., 1994). These efforts have, thus far, failed to provide conclusive evidence for a particular .alpha..sub.1 -adrenoceptor subtype being responsible for the effects of adrenoceptor agonists in the urethra.
This invention relates to the discovery that .alpha..sub.1C -agonists are useful for the treatment of urinary incontinence with the potential for decreased side effects. Data already exists which indicates that the .alpha..sub.1C -adrenoceptor is not involved significantly in the cardiovascular actions of .alpha.-agonists and antagonists (Forray et al., 1994). Therefore, agonists exhibiting significant binding and functional selectivity for the .alpha..sub.1C -adrenoceptor over other .alpha..sub.1 -adrenoceptors, .alpha..sub.2 -adrenoceptors, .beta.-adrenoceptors, as well as histamine receptors and serotonin (5-HT) receptors, are contemplated to be more effective agents, relative to currently available therapies, for the treatment of urinary incontinence.